1. Field of the Invention
The invention generally relates to the use of estrogens and antiprogestins for the treatment of hormone related conditions.
2. Description of the Relevant Art
With the onset of menopause in women, so-called menopausal symptoms occur owing to altered hormone production, reduced estrogen production lead to increased risk of osteoporosis and other symptoms like hot flashes, sweating and mood swings.
Hormone replacement therapy (HRT) with estrogens or an estrogen/progestin combination is currently the standard method of treatment for such symptoms. Benefits and risks of menopausal estrogen and/or progestin use have been well documented.
One of the risks of HRT is an increased risk of endometrial carcinomas. The use of simultaneous treatment of estrogen with a progestin can mitigate these risks. Progestins suppress the stimulating effect on the endometrium caused by estrogens.
One point of great concern of such combination therapy (estrogen/progestin treatments) is that many progestins lead to an increase in breast cancer risk. Thus, the current therapies for reducing or preventing symptoms of menopause are not ideal.
The search for alternative therapies lead to a combination of an antioestrogen with an antiprogestin and the use of a combination of estrogens and antiprogestins in a sequential manner.
For numerous antiprogestins, antiproliferative activity in vitro and antitumor effect in animal models has been reported for compounds such as RU 486, Onapristone, and ZK 230 211. All the reported compounds however belong to the class of pure progesterone receptor antagonists that lack partial agonistic activity. Such compounds are therefore not suitable for a combination therapy with estrogens. Such compounds lead to side effects of unopposed estrogenicity, such as endometrial hyperplasias or endometrial cancer.
Compounds possessing both agonistic and antagonistic activity have been reported in the past. However, the use of such compounds in a combination therapy with estrogens has not, to our knowledge, been described.
Another approach to an improved treatment of menopausal symptoms is described in U.S. Pat. No. 6,479,535. A combination of conjugated estrogens with estrogen antagonists (e.g., Bazedoxifene) was described. This combination has been described to have, besides positive effects on menopausal symptoms, the ability to block the growth of occult breast cancer neoplasms in postmenopausal women, and thus should lead to an overall reduction in tumor incidence. The disadvantage of conjugated estrogens with estrogen antagonists is inferior bleeding profile compared to standard estradiol progestin combinations. In a group of postmenopausal women the incidence of irregular bleeding during cycle 9 is 11% for a 1 mg E2/0.5 mg META combination and 25.8% for 0.625 mg CEE (conjugated estrogen)/5 mg MPA. The cumulative rate of amenorrhea in postmenopausal women is around 90% and around 80% in perimenopausal women. Bazedoxifene/conjugated estrogens showed only an 83% incidence of amenorrhea in the first year of treatment in postmenopausal women.
In summary it can be concluded that there is still a high medical need for an effective treatment of menopausal complaints with an excellent bleeding control for postmenopausal and perimenopausal women. In addition such treatment should have a preventive effect on the occurrence of breast cancer.